The incidence of insulin resistance, metabolic syndrome, and type 2 diabetes is rising rapidly due to the obesity epidemic in the industrialized world. The leading cause of morbidity and mortality in insulin resistance is atherothrombotic cardiovascular disease. However, the molecular and cellular mechanisms linking insulin resistance to atherothrombosis are poorly understood, in part because this area falls between two distinct fields of research. The proposed PPG will bring together experts in these different areas to elucidate novel signal transduction pathways that contribute to accelerated atherosclerosis in insulin resistance. The PPG focuses on two key processes in this arena: (1) death of macrophages (Mfs) in advanced atherosclerosis, which is accelerated in insulin resistance and gives rise to the necrotic core of vulnerable plaques;and (2) hepatic production of atherogenic lipoproteins, which is perturbed in insulin resistance and leads to dyslipidemia. Each project is based on key mechanistic and in-vivo data obtained collaboratively by the PPG investigators. In Project 1, Dr. Tabas will focus on a novel, multi-hit pro-apoptotic signaling pathway in Mfs that is promoted by both Mf insulin resistance itself and by systemic insulin resistance through reduction in adiponectin, an adipocytokine that the Tabas lab found suppresses apoptosis signaling in Mfs. In Project 2, Dr. Tall, in collaboration with Projects 1 and 3, will investigate the molecular connections between Mf insulin resistance and downstream apoptosis effectors, with a focus on Akt and FoxO signaling. Project 2 will also complement the studies in Project 3 by studying the molecular mechanisms of how selective hepatic insulin sensitivity prevents atherogenic dyslipidemia. In Project 3, Dr. Accili will work with Dr. Tall to study how selective hepatic insulin resistance leads to atherogenic dyslipidemia, with a focus on transcriptional regulation by FoxO1. Dr. Accili will also collaborate with Drs. Tabas and Tall to investigate the role of FoxO as a mediator of apoptosis signaling in Mfs. Each project will be supported by the Lesion Analysis/ Biostatistics Core, in which Dr. Welch's team will provide assistance and expertise in mouse atherosclerosis assays and in biomathematics. The synergistic and highly interactive nature of these projects and the complementary expertise in atherosclerosis and insulin signaling among the PPG investigators will enable a unique opportunity to address the emerging epidemic of insulin resistance-associated heart disease.